Polymer micelles are one type of nanovector formed by the aqueous assembly of block copolymers that are polymer chains containing both hydrophilic and hydrophobic portions. These structures often exist as spherical particles with a core-shell morphology and sub-micron diameter. The design of nanovectors, such as block copolymer micelles, that effectively mimic the selectivity and evasiveness of viral particles remains a major goal of drug delivery research.
The chemotherapeutic agent paclitaxel (PTX), a microtubule-interfering agent, has demonstrated a broad spectrum of antitumor activity against various cancers including breast, lung and advanced ovarian cancers. The low solubility of PTX and the difficulty of achieving sufficiently high concentration in solution that is suitable for in vivo administration and clinical applications have led to the development of various strategies to increase its bioavailability, which utilize low molecular weight surfactants (e.g., Taxol®), coat the drug with albumin (e.g., Abraxane®), or conjugate it to water-soluble polymers (e.g., PTX poliglumex, OPAXIO™, CT-2103, Xyotax®). Other delivery mechanisms for PTX that have been developed include a number of degradable and non-degradable drug conjugates, such as PTX-conjugated polyvalent DNA-functionalized gold nanoparticles, polylactide (PLA)-PTX conjugated nanoparticles and PTX cross-linked PLA-based nanocomposites.
However, there are several challenges with the formulation of PTX that remain unmet. For example, present formulations fail to achieve the desired high PTX loading (e.g., due to reaction non-selectivity in many present formulations) while also maintaining high water solubility so as to be suitable for in vivo administration and clinical applications. Also, the toxicity and hypersensitivity reactions associated with vehicles for the delivery of many present formulations of PTX (e.g., Cremophor-EL, polyethoxylated castor oil) remain problematic.
The present disclosure addresses these needs, among others, by providing compounds, methods for synthesizing compounds, and formulations and applications of compounds, that, in some embodiments, achieve high loading of PTX, increase PTX solubility, and other chemotherapeutic agents, and that exhibit low toxicity, allow controlled PTX release kinetics, and are capable of extended circulation in vivo, and have a possibility of versatile chemical modifications—for instance, the conjugation of imaging agents and/or targeting ligands.